Many nucleoside analogues with potential for the treatment of AIDS are not effected at inhibiting replication of human immunodefiency virus (HIV) because they are not efficiently metabolized to the active triphosphates in infected cells. In this proposal we describe approaches to overcome this problem. Various structural classes of nucleotide analogues will be synthesized and investigated for their ability to give rise to the active triphosphates in HIV-susceptible cells. The inhibitory activity of these metabolites against purified reverse transcriptase will be determined. In addition, the new compounds will be directly evaluated for antiviral activity against HIV-infected H9 cells.